The purpose of this project is to determine the natural course of renal disease in type 2 diabetes mellitus in the Pima Indians and to identify the underlying pathogenetic mechanisms involved in the initiation and progression of renal disease in this type of diabetes. This project, in part, represents an extension of work previously reported as Project Number Z01 DK 69037. Glomerular function was measured over a 4-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. Follow-up was extended for an additional 24 months in the 57 subjects with microalbuminuria to characterize the evolution and mechanisms of progressive diabetic glomerular injury. Subjects underwent serial determinations of albuminuria and GFR, and a subset of them underwent morphometric analysis of glomeruli in two biopsies separated by an interval of 48 months. GFR declined by 16% and renal plasma flow by 17% over 60-84 months, regardless of whether or not subjects progressed to macroalbuminuria. Neither glomerular volume nor fractional mesangial volume changed over 48 months, but the prevalence of global glomerulosclerosis doubled and the number of podocytes per glomerulus declined significantly from 547 to 356. Single nephron Kf declined by 20% and was the major determinant of the decline in GFR. We found recently that lower podocyte number is the most important morphometric predictor of progressive renal disease in Pima Indians. The present study suggests that podocyte destruction in early diabetic nephropathy rather than inherent phenotypic variability is responsible for this finding. Elucidation of the mechanisms responsible for the podocyte desctruction offers hope for improved renoprotective therapy. - Natural history, type 2 diabetes, diabetic nephropathy, renal morphometry, epidemiology - Human Subjects